I. Field of the Invention
This invention relates to regulation of cell signaling and cell growth, and more particularly to the regulation of cancer or immune cell growth.
II. Description of Related Art
The MUC1 heterodimeric mucin-type glycoprotein is expressed on the apical borders of secretory epithelial cells (Kufe et al. (1984) Hybridoma 3:223-232). With transformation and loss of polarity, MUC1 is expressed at high levels over the entire cell membrane and in the cytoplasm (Kufe et al. (1984) Hybridoma 3:223-232). The MUC1 N-terminal ectodomain, which consists of variable numbers of 20 amino acid tandem repeats that are extensively modified by O-linked glycans, is tethered to the cell surface through a complex with the MUC1 C-terminal transmembrane subunit (MUC1-C) (Siddiqui et al. (1988) Proc. Natl. Acad. Sci. USA 85:2320-2323; Gendler et al. (1988) J. Biol. Chem. 263:12820-12823; and Merlo et al. (1989) Cancer Res. 49:6966-6971). MUC1-C integrates receptor tyrosine kinase signaling with the Wnt pathway (Li et al. (1998) Mol. Cell. Biol. 18:7216-7224; Li et al. (2001) J. Biol. Chem. 276:35239-35242; and Li et al. (2001) J. Biol. Chem. 276:6061-6064). MUC1-C is also targeted to mitochondria and to the nucleus, where it contributes to the regulation of β-catenin/Tcf- and p53-mediated gene transcription (Ren et al. (2004) Cancer Cell 5:163-175; Huang et al. (2003) Cancer Biol. Ther. 2:702-706; and Wei et al. (2005) Cancer Cell 7:167-178). Overexpression of MUC1 is sufficient to induce transformation and to attenuate apoptosis in the response of cells to oxidative and genotoxic stress (Ren et al. (2004) Cancer Cell 5:163-175; Huang et al. (2003) Cancer Biol. Ther. 2:702-706; Li et al. (2003) Oncogene 22:6107-6110; Raina et al. (2004) J. Biol. Chem. 279:20607-20612; and Yin et al. (2004) J. Biol. Chem. 279:45721-45727).
Heregulin (HRG) induces MUC1 expression in MCF10A cells. HRG increases (i) c-Src-mediated phosphorylation of MUC1-C on Tyr-46, (ii) binding of MUC1-C and HSP90, and (iii) targeting of MUC1-C to the mitochondrial outer membrane (MOM) in breast cancer cells (Ren et al. (2006) Oncogene 25:20-31). Unlike breast cancer cells, little if any MUC1-C is detectable in mitochondria of MCF10A cells.
MUC1-C localizes to the MOM and blocks release of mitochondrial apoptogenic proteins (Ren et al. (2004) Cancer Cell 5:163-175; Ren et al. (2006) Oncogene 25:20-31; Yin et al. (2002) J. Biol. Chem. 277:17616-17622). How MUC1-C regulates mitochondrial outer membrane permeabilization (MOMP), which allows release of proteins in the intermembrane space to diffuse in to the cytosol (Green et al. (2005) Cell 121:671-674), is not known. However, information is available regarding the role of Bcl-2 family members in regulating MOMP. The proapoptotic BH3-only proteins (e.g., BID, BIM) interact with the multidomain proapoptotic BAX and BAK, which in turn oligomerize to form a pore in the MOM that is essential for permeabilization (Wei et al. (2001) Science 292:727-730; Kuwana et al. (2002) Cell 111:331-342). The BH3-only proteins can also neutralize the multidomain anti-apoptotic (e.g., Bcl-2, Bcl-xL) proteins that block BAX and BAK oligomerization (Certo et al. (2006) Cancer Cell 9:351-365).